Despite intensive effort to understand the brain substrates of cocaine addiction through biochemical investigations in the experimental animal, the cause of cocaine addiction remains unknown. We suggest that such neurochemical studies should also be conducted in brain of the human cocaine user. In an autopsied brain study of ten cocaine users, we observed reduced concentration of a specific neurotransmitter, dopamine (DA), in the nucleus accumbens--a brain area suggested to be involved in mediating both the acute and long-term effects of cocaine. The SPECIFIC AIMS of our proposed investigation are to examine the reliability and reversibility, cause, and drug and neurochemical specificities of the DA reduction. Our major HYPOTHESIS to be tested is that withdrawal from cocaine and other drugs of abuse will be associated with reductions in levels of nucleus accumbens DA, DA biosynthetic enzymes, and DA transporter, that are eventually reversed. This hypothesis will be tested through biochemical examination, by HPLC, Western Blot, and autoradiographic approaches, of levels of DA, the DA biosynthetic enzymes tyrosine hydroxylase and DOPA decarboxylase, and the DA transporter in autopsied brain of a minimum of ten cocaine, five opiate, five methamphetamine, and five alcohol users during each of the three years of our investigation. A special feature of this study is our ability to obtain, from U.S. medical examiners, autopsied brain of drug users characterized with respect to drug type, duration, and pattern. We expect that the results of our investigation will provide a robust test of the "DA depletion hypothesis of cocaine addiction" and, at the same time, will address the important medical issue of cocaine toxicity to human brain DA neurones. Ultimately, this information will help to clarify the contribution of the nucleus accumbens DA system to the behavioral consequences, and possibly causes, of cocaine use in the human and contribute to the development of new brain region-based approaches to the problem of drug addiction.